Mechanical Variability of the Heart
Various cardiovascular variables demonstrate beat-to-beat variability around a constant or slowly changing mean value: Heart-rate variability (the beat-to-beat variability of cardiac cycle length, Woo et al., "Patterns of beat-to-beat heart rate variability in advanced heart failure". American Heart Journal. 123(3):704-10, 1992), blood pressure variability (Parati et al, "Neural cardiovascular regulation and 24-hour blood pressure and heart rate variability", Annals of the New York Academy of Sciences. 783:47-63, 1996), QT-interval variability and dispersion, the temporal and spatial variability of myocardial relaxation (Barr et al., "QT dispersion and sudden unexpected death in chronic heart failure", The Lancet. vol. 343:327-329, 1994), T-wave alternans (Verrier and Nearing, "Electrophysiologic basis for T-wave alternans as an index of vulnerability to ventricular fibrillation", Journal of Cardiovascular Electrophysiology, 5:445-461, 1994). Most of these indices are derived from the ECG and thus represent variabilities of electrical activation and relaxation mechanisms, either directly due to inherent factors or indirectly induced by other mechanisms (e.g. the effect of breathing on heart rate and blood pressure variabilities). Since mechanical variability is associated with electrical variability through electrical-mechanical coupling, partial information about mechanical variability can be gained from the electrical variability. However, there is no methodology and apparatus for direct evaluation of mechanical variability of myocardial activity, namely variability in the contraction, relaxation and filling phases of the heart cycle.
The aforementioned variability indices were demonstrated to be clinically useful in the evaluation of heart failure (Woo et ale. "Patterns of beat-to-beat heart rate variability in advanced heart failure", American Heart Journal. 1223(3):704-10, 1992), risk of sudden-death (American College of Cardiology Cardiovascular Technology Assessment Committee, "Heart rate variability for risk stratification of life-threatening arrhythmias", Journal of the American College of Cardiology, 22(3):948-50, 1993; Barr et al., "QT dispersion and sudden unexpected death in chronic heart failure", The Lancet, 343:327-329, 1994), vulnerability to arrhythmia (e.g. Verrier and Nearing, "Electrophysiologic basis for T-wave alternans as an index of vulnerabilily to ventricular fibrillation", Journal of Cardiovascular Electrophysiology, 5:445-461, 1994). These methodologies do not directly evaluate the mechanical variability of the heart and cannot provide cardiac regional variability. For many patients with regional myocardial injuries (like acute myocardial infarct), these methodologies may not be sensitive enough to contribute to the diagnosis. Accordingly, there is a need for a non-invasive methodology which can directly measure mechanical variability both globally (for the whole heart) and locally, and thus increase the sensitivity and specificity of correct diagnosis of various cardiac diseases.
Ultrasound Contrast Imaging
Ultrasound contrast imaging, the use of contrast agents to enhance ultrasound-derived images, is clinically useful to enable better evaluation of the scanned structures (e.g. enhancement of cardiac chambers) or to enable quantitative assessment of blood perfusion to various organs. Compared with other contrast-enhanced imaging modalities, like CT and MRI, ultrasonic imaging is simpler, faster and less expensive (Thomas J D, Griffin B P, White R D, "Cardiac imaging techniques: which, when, and why", Cleveland Clinic Journal of Medicine, 63(4):213-20, 1996).
Although currently available contrast agents significantly enhance ultrasound imaging and enable assessment of blood perfusion to various organs (Porter T R, Li S, Kricsfeld D, Armbruster R W, "Detection of myocardial perfusion in multiple echocardiographic windows with one intravenous injection of micro bubbles using transient response second harmonic imaging", Journal of the American College of Cardiology, 29(4):791-9, 1997), there is a need to further enhance the ultrasound-derived images in order to achieve efficacy comparable to other imaging modalities. This can be achieved by development of better contrast agents, or by enhancing the contrast agent effect through specifically designed ultrasound systems or ultrasound image modalities. The second-harmonic and power harmonic (Porter T, Xie F, Kricsfeld D, Armbruster R W, "Improved myocardial contrast with second harmonic transient ultrasound response imaging in humans using intravenous perfluorocarbon-exposed sonicated dextrose albumin", Journal of the American College of Cardiology, 27(6):1497-501, 1996) are examples of contrast enhancement through changes in the ultrasound scanning technology. Yet another potential approach is to achieve the enhancement through processing of the ultrasound-derived images. Kaul and colleagues have used image subtraction methodology to enhance the contrast effect for myocardial perfusion studies (Kaul S, "Myocardial Contrast Echo", Current Problems in Cardiology, 22(11):572-582, 1997). They have averaged several pre-contrast images and several with-contrast images and then subtracted the two averages to achieve an image composed mainly of the change between the pre-contrast and the contrast states. However, due to the random nature of the echoes from the bubbles the averaging process result in attenuation of the contrast effect.
Objects of the Invention
It is therefore an object of the present invention to provide a method and apparatus for the evaluation of myocardial variability through the measurement of the variability of ultrasound-derived images of the heart.
It is another object of the present invention to present the variability of the image of the heart using easily interpreted display for various clinical applications.
It is another object of the present invention to provide a method and apparatus for the enhancement of contrast ultrasound imaging through variability analysis of the contrast-echo images, either in real-time or by off-line analysis.
It is another object of the present invention to enhance blood-pool images (e.g. heart chambers) through variability analysis of the contrast-enhanced images.
Yet another object of the present invention is to enable quantitative assessment of the dynamics of blood perfusion to various organs and tissues based on variability analysis of the contrast-enhanced images.
Still another object of the present invention is to develop a methodology to present the enhanced contrast-echo image to the operator through either real-time or off-line image display.
In general, variability of an imaged object can be assessed by acquisition of multiple images and evaluation of the variation of the acquired images of the object. When the imaged object is the beating heart, or when one is interested in blood perfusion or flow, a difficulty arises due to the dynamic change of the cardiac shape or the pulsatile nature of blood flow. This can be overcome by comparing images acquired during the same phase of heart activity, which can be achieved by gating the images to a specific event which marks a specific phase at each cycle. The use of the R-wave of the ECG for gating the scanned images of cardiologic echo-Doppler system to achieve image enhancement by averaging the gated images was disclosed in a co-pending provisional patent application Ser. No. 60/018,466 of Nevo et al., filed May 28, 1996, now PCT/US97/09455, published Dec. 4, 1997 as WO 97/45058.
The current invention uses the gated images to evaluate the variability of the mechanical activity of the beating heart. The heart cycle is divided into "m" equal sequences, which are timed with respect to a fiducial point on the QRS complex, like the tip of the R-wave. Gating the acquired images of the heart eliminates the temporal variation of the image due to functional movement of heart structures (during contraction, relaxation and filling of the cardiac chambers). The gated images, namely images with the same time delay in reference to the R-wave, represent the heart during the same phase of the cardiac cycle, and should be similar if there is no variability in the heart function. Actually, the images are not identical and differ to some extent from each other. The level of variation of each image, compared with the mean (the average of all images with the same time delay), represents the mechanical variability of the heart at the specific time point during the heart cycle. This information can be displayed by various methodologies, for example by a color coding scheme which assigns a different color to each level of variability. Ideally, the variability is estimated in real-time and displayed to the operator when the image is acquired. This approach can be applied with all modes of commercial echo-Doppler systems, namely 2-dimensional mode, m-mode, Doppler, color-Doppler, tissue-Doppler and 3-dimensional imaging.
The micro-bubbles of the contrast agents create highly variable echoes. Echoes coming from the same spatial point but at different times (e.g. once during each heart cycle) are variable and result in a variable ultrasound image (i.e. different gray level of a specific pixel at different times). In contrast, structural elements like myocardium generate less variable echoes and result in more stable gray level of the ultrasound image.
Similarly, R-wave gating can be used to enhance the 2-dimensional image of the heart or the Doppler image of blood flow during contrast ultrasound imaging.
Unlike cardiac variability imaging, which requires gating to the R-wave to prevent image smearing, variability of non-cardiac structures and tissues can be assessed without gating. This may be useful when one expects different levels of pulsatility of blood perfusion in a certain scanned area. For example, it is well documented that blood vessels in tumors of certain tissue, are different than blood vessels in the normal tissues. The different mechanical and anatomical properties of the blood vessels result in different level of blood vessel pulsations induced by the inflowing blood. This may result in different levels of variability of the tumor area compared with the normal tissue, and may be of use to delineate abnormal from normal tissue by contrast ultrasound imaging.
Another application of variability analysis of consecutive images is to quantify the dynamics of transient appearance ("first pass") or disappearance ("wash-out") of the contrast agent. The current approach of video densitometry is based on assessment of the gray level of the pixels in a specific region of interest (ROI) either at a specific phase of the heart contraction or at consecutive frames, and the generation of "activity curve" which provides the temporal change of gray level of these pixels. The current invention enables real-time measurement of the dynamic of blood perfusion across the whole 2-D image and for all phases of cardiac contraction through automatic variability analysis. It thus significantly enhances the current available technology for quantitative assessment of tissue blood perfusion.
The current invention uses either real-time or off-line image variability analysis to enhance the effect of contrast agents during ultrasound scan of specific organ or tissue. For enhancement of cardiac blood-pool (i.e. heart chambers) and myocardial perfusion, or to assess the pulsatile perfusion to any non-cardiac structure, the heart cycle is divided into "m" equal sequences, which are timed with respect to a fiducial point on the QRS complex, like the tip of the R-wave. Gating the acquired images of the heart prevents smearing of the image by the elimination of the temporal variation of the image due to functional movement of heart structures. Similarly, additional gating to breathing cycle may eliminate image smearing due to breathing-induced movements of the scanned structures.
Quantification of blood perfusion to myocardium or other tissues can be achieved by either imaging of a transient appearance of the contrast agent ("first pass") or by steady-state, equilibrium imaging. Initiating the variability assessment with contrast-free image, and continuing through the appearance of the contrast agent until it achieves a full contrast effect, results in high variability of regions having high content of blood. Yet first pass imaging is available once for every injection of the contrast agent, and steady state assessment is required as well. The high temporal variation of the contrast agents, which stem from the random appearance of the micro-bubbles at different times, compared with the relatively low variability of structural elements (e.g. myocardium), results in improved delineation between anatomic structures or tissues with poorly perfused areas, compared with echoes from blood pool regions or well-perfused regions.
The enhanced images can be displayed by various methodologies. The basic display is with grey-level images, were the processed images (the variability image or the ratio between the variability image and the average image) benefit from the improved contrast between the structural components (e.g. myocardium) and the contrast-enhanced regions (e.g. blood pools). To enhance the discrimination between these regions the display can use a color coding scheme which assigns a different color to each level of variability, or contour plots overlayed over the raw image or over the averaged image. Ideally, the variability is estimated in real-time and displayed to the operator when the image is acquired. However, the analysis and display can be done from video or digitally recorded studies. The proposed methodology can be applied with all modes of commercial echo-Doppler systems which are used with contrast imaging, namely 2-dimensional (B-mode) by either fundamental frequency, second harmonic or power harmonic imaging, flow imaging by Doppler and color Doppler mode, and m-mode.
The invention also discloses apparatus to enable the application of the described method either as an external add-on device for commercial echo-Doppler systems or as a built-in module installed within the echo-Doppler systems. The apparatus comprises an interface to acquire the image from the echo-Doppler system, an interface to obtain the gating signal, memory modules to save the gated images, user interface to control parameters of the algorithm, micro-processor for mathematical processing of the images, and an interface to present the averaged image and its variability.